Synthesis andEvaluation of Cyclic Peptide-Based PETTracers Targeting ADAMTS4 for Early Detection and Monitoring of AorticAneurysms

Abstract Aortic aneurysm (AA), with high rupture risk and mortality, lacks accurate early diagnostic tools. Existing morphological imaging and [18F]FDG PET show insufficient specificity, necessitating AA-specific tracers. In this study, ADAMTS4, a regulator of vascular wall cell proliferation and collagen repair, was verified as a potential biomarker with high expression in human AA tissue. Based on an ADAMTS4-targeting peptide, PET tracer precursor series (ADA1–ADA5) with varied linkers were designed and synthesized, aiming to optimize pharmacokinetic properties. Binding assays revealed that ADA2 showed the highest ADAMTS4 binding affinity among all, with ∼4-fold improvement compared to unmodified peptide ADA0. Next, [68Ga]ADA1–[68Ga]ADA5 with satisfactory radiochemical properties were obtained and subjected to PET/CT imaging. [68Ga]ADA2 exhibited optimal AA uptake and the ability to localize ∼20% dilated aorta. Furthermore, the tracer demonstrated favorable in vivo safety and reduced renal uptake, highlighting its promise for the early detection of AA progression and the identification of high-risk patients.